The town was first mentioned in 1399 as "Jagodna", derived from the Serbian word for 'strawberry' - Jagoda. From 1946 to 1992 the town was renamed Svetozarevo (Serbian: Светозарево, [sʋetozǎːreʋo]) after the 19th-century Serbian socialist Svetozar Marković.

"Juhor-type" gold bracelets dating from the Middle Bronze Age have been found in Trcevac. Remains of a Bronze Age settlement were found in a part of town called Sarina Međa. In the village of Belica, near Jagodina, the Europe's oldest sanctuary is found. In the early Neolithic settlement, the world's largest collection of prehistoric artefacts was found, with nearly a 100 manlike figures made of stone, bones and clay, about 8000 years old. Geophysical research in 2012. in the area of Belica uncovered a prehistoric settlement, surrounded by a circular trench that has a 75 meters long diameter. Inside that circle, triangular, trapezoid and circular shaped foundations of monumental structures were found, unlike any found in other early Neolithic settlements.

On top of mountain Juhor there was a Celtic oppidum, and in the village of Novo Lanište a Triballi settlement. With the Roman conquest of 74. BCE, the territory of today's Jagodina falls under the Roman authority. Romans had a castel on the hill Đurđevo Brdo, and the settlement beneath it. Ad Octavium was a spot on the military road upon which today stands the village Dražmirovac.

Coins of Emperor Phokas and Constantine IV from 643/4 and fibulae have been found in the region, as well as Early Slavic pottery dating to the 6th century.[3] In 1183. Grand Prince Stefan Nemanja had liberated the areas of Belica, Levač and Lepenica from the rule of Byzantine Empire. Jagodina was situated in the Belica county. The first time Jagodina was mentioned was in 1399. in a letter to Princess Milica (the wife of Prince Lazar Hrebeljanović), and the second time was in 1411. when the Parliament was held there. After the year 1458, Jagodina falls into the hands of the Ottoman Empire. During the secound half of the 15th century, in the Ottoman Empire's tax registers, certain Miloš Belmužević is mentioned as the landlord of Jagodina. He later fled to Hungary.

During the middle of the 16th century Jagodina becomes a feud of a Dervish-bey Jahjapašić. A large mosque is built there in 1555, and sometime latter, another one. Jagodina had two caravan stations and a public bathroom. In Jagodina, by the command of Dervish-bey, certain German clockmaker built a clock tower, which was a rarity in Ottoman Empire at the time. In 1553-1557 the travelers refer to Jagodina as a beautiful settlement with 4 caravan stations and two mosques. In it lived more of sipahis and Ottoman soldiers, and less Christian Serbs. It had a Turkish school. With the status of a palanka (small town), Jagodina is mentioned in 1620, as a small stop on the road to Istanbul. In the year 1660, a traveler named Evlija Čelebija states that the town has 1500 houses and that the entire population is made of Christians that were converted to Islam. In the middle of the 17th century Jagodina gets its own bedesten. After the Austrian-Turkish war (1716-1718), Jagodina becomes the capital of the District of Jagodina. According to Austrian register in 1721. Jagodina had 162 families living in it. After the new Austrian-Turkish war (1737-1739), Serbia is back under the Ottoman rule.

During the Serbian Revolution (1804–1817), when Serbs began their uprising against the centuries-long Ottoman rule, Jagodina was a scene of numerous battles, given the town's strategic importance within Serbia proper. Following the Ottoman defeat and re-establishment of the Kingdom of Serbia, Jagodina experienced a period of relative industrial and civic development. From 1929 to 1941, Jagodina was part of the Morava Banovina of the Kingdom of Yugoslavia. Following World War II, Jagodina was heavily industrialized and underwent a period of planned expansion and growth within communist Yugoslavia.

According to the 2011 census, ethnic groups in the municipality of Jagodina include 68,898 Serbs, 764 Roma, 41 Romanians, 67 Yugoslavs, and others.

In the aftermath of the Serbian independence regained from the Turks in the early 19th century, Turkish families moved out of Jagodina. The last Turkish family left Jagodina in 1832, and the town has been ethnically homogenous (Serbian) ever since. By 1837 Jagodina had 5,220 inhabitants, while Serbia proper had a population of 41,374. In the 1866 census, there were 4,429 citizens. In 1876 Jagodina was still an agricultural town with 91.88% of the population being in some way associated with agriculture.

By the 1930s Jagodina had 6,950 citizens, and by the 1960s the town had 19,769 inhabitants. By 1971 the number grew to 27,500. In the previous census held in 1991 the Jagodina municipality had 77,000 citizens while the town itself had 36,000. In the last census from 2002, the Jagodina municipality had 70,894 residents and Jagodina town 35,589. It was given the status of a city in 2008. It is evaluated that the city of Jagodina itself has between 55000 and 60000 inhabitants now. The next census will be held after 2010.

Jagodina opened its zoo on July 10, 2006, at a cost of 30 million Serbian dinars. The municipality invested 40% and donors provided 60% of the costs while the biggest donor was the Belgrade Zoo. The zoo is located in the complex of the city park "Đurđevo brdo", a designated nature park, with an area of 20,074 square meters. It has pedestrian zones for children, the old and disabled persons, and generally a high-quality infrastructure.

The Jagodina Zoo is the third largest in Serbia, next to Belgrade and Palić. It currently houses some 100 different species of animals.

The first primary school in Jagodina was opened in 1808. Today, there are 11 primary schools in Jagodina of which 6 are in the city and five are in the rural area, with 36 regional offices. There are also 4 secondary schools and two universities, one public (founded in 1898) and one private (Megatrend University).

Jagodina was heavily industrialized following World War II. The biggest factory in Jagodina is the cable factory. The Cable Factory Jagodina (FKS) was founded in 1947 and regular production started in 1955. In addition to cables, FKS produces connectors and similar cable products. FKS employs about 8,000 workers, and it is the biggest Serbian cable factory. 50% of the total Serbian production of the cable industry is produced in Jagodina. FKS is one of the biggest Serbian exporters of cable products. About 2/3 of its production is placed on the foreign market, representing more than 60% of the total exports of the Serbian cable industry.

Total length of roads in the city of Jagodina is 248 km (154 miles). There are 5 regional roads, 86 km (53 mi) long and 32 local roads, 162 km (101 mi) long. Except for the international highway E-75 (section Belgrade - Nis), which goes by the city for about 30 km (19 mi), there are no other major roads here. As for the roads of regional significance, the following pass through the town:

An electric double-track railway goes through Jagodina which connects Central Europe with Southern Europe and Asia.Total length of railway network in the city is 34 km (21 mi), of which 28 km (17 mi) are electric. Railway stations in Jagodina are: